The Role of Risk The Role of Risk Information in Product Information in Product

LabelingLabeling

Catherine Gray, PharmDCatherine Gray, PharmDManagement AdvisorManagement AdvisorDivision of Drug Marketing, Advertising, and Division of Drug Marketing, Advertising, and CommunicationsCommunicationsCenter for Drug Evaluation and ResearchCenter for Drug Evaluation and ResearchIMMPACT Annual MeetingIMMPACT Annual MeetingJune 17, 2011June 17, 2011

ObjectivesObjectives

Explore FDA’s role in regulating Explore FDA’s role in regulating prescription drug promotion and prescription drug promotion and advertising.advertising.

Discuss the impact of product labeling in Discuss the impact of product labeling in advertising and promotion.advertising and promotion.

Review several examples of false or Review several examples of false or misleading promotion of prescription misleading promotion of prescription analgesic drug products.analgesic drug products.

Division of Drug Marketing, Division of Drug Marketing, Advertising, and Advertising, and

Communications (DDMAC)Communications (DDMAC) Protect the public health by assuring prescription Protect the public health by assuring prescription

drug information is truthful, balanced and drug information is truthful, balanced and accurately communicated. accurately communicated.

Accomplished through a comprehensive Accomplished through a comprehensive surveillance, enforcement and education surveillance, enforcement and education program, and by fostering better communication program, and by fostering better communication of labeling and promotional information to both of labeling and promotional information to both healthcare professionals and consumers.healthcare professionals and consumers.

FDA StructureFDA Structure

Food and Drug Administration

CDERCenter for

Drug Evaluation

and Research

CBERCenter for Biologics

Evaluation and

Research

CDRHCenter forDevices

andRadiological

Health

CFSANCenter for

FoodSafety

and AppliedNutrition

CVMCenter forVeterinaryMedicine

CTPCenter forTobaccoProducts

ORAOffice of

RegulatoryAffairs

What Does DDMAC What Does DDMAC Regulate?Regulate?

Written and printed prescription drug Written and printed prescription drug promotional materials made by the company promotional materials made by the company which include:which include: TV and radio commercialsTV and radio commercials Sales aids, journal ads, and patient brochuresSales aids, journal ads, and patient brochures Drug websites, e-details, webinars, Epocrates, and Drug websites, e-details, webinars, Epocrates, and

email alertsemail alerts Oral Presentations made by representatives Oral Presentations made by representatives

of the company which include:of the company which include: Sales RepsSales Reps Hired Spokespeople Hired Spokespeople Medical Science LiaisonsMedical Science Liaisons

Total # of Promotional Total # of Promotional PiecesPieces

6877 8,632 14970 1696510,901 12,616 14456 15998 15930

43,235 47,040 45663 45571

61,01368,288 71085

76631 78466

6223

45712

0

20000

40000

60000

80000

100000

2006 2007 2008 2009 2010

Mixed Consumer Professional Total

What does DDMAC do?What does DDMAC do?

Advice to industryAdvice to industry Advice within FDAAdvice within FDA Surveillance and Enforcement Surveillance and Enforcement Guidances and Policy Guidances and Policy

DevelopmentDevelopment ResearchResearch

Advice to IndustryAdvice to Industry

Provide comments on DRAFT promotional Provide comments on DRAFT promotional materials (VOLUNTARY in most cases)materials (VOLUNTARY in most cases) Launch materials for new drugs or new Launch materials for new drugs or new

indicationsindications Direct-to-consumer (DTC) broadcast adsDirect-to-consumer (DTC) broadcast ads Non-launch materialsNon-launch materials

Pre-submission required for certain drugsPre-submission required for certain drugs(e.g., Subpart H “accelerated approval”)(e.g., Subpart H “accelerated approval”)

Advice within FDAAdvice within FDA

Provide consultation on:Provide consultation on: Draft labelingDraft labeling Cartons and product labelsCartons and product labels Medication GuidesMedication Guides Patient Package Inserts (PPIs)Patient Package Inserts (PPIs) Dear Doctor lettersDear Doctor letters Pharmacoeconomics, health-related Pharmacoeconomics, health-related

patient-reported outcome protocolspatient-reported outcome protocols

SurveillanceSurveillance

Review materials submitted to DDMAC at the Review materials submitted to DDMAC at the time of initial disseminationtime of initial dissemination

ConferencesConferences ComplaintsComplaints

Healthcare professionalsHealthcare professionals ConsumersConsumers LawyersLawyers CompetitorsCompetitors

Enforcement Action – Enforcement Action – LettersLetters

Pertain to pieces in the public domainPertain to pieces in the public domain Public letterPublic letter Untitled Letter versus Warning LetterUntitled Letter versus Warning Letter

WL issued for more egregious or repeat WL issued for more egregious or repeat violationsviolations

ImpactImpact Expect immediate cessation of violative claims Expect immediate cessation of violative claims

and presentationsand presentations Corrective message expected for WLCorrective message expected for WL

How Does the PI Affect How Does the PI Affect DDMAC?DDMAC?

Primary reference for the evaluation of a Primary reference for the evaluation of a promotional piecepromotional piece

Content in the PI cannot be restricted from Content in the PI cannot be restricted from use in promotional materialsuse in promotional materials No role for promotion in the PINo role for promotion in the PI

ConsistencyConsistency Within a single PI and across a drug categoryWithin a single PI and across a drug category Language in Highlights, Warnings & Language in Highlights, Warnings &

Precautions, and Adverse Reactions SectionsPrecautions, and Adverse Reactions Sections

Framing RiskFraming Risk

Important not to minimize the dataImportant not to minimize the data ““Is associated with…”Is associated with…” ““There were reports of…”There were reports of…” ““Causes…”Causes…”

Theoretical versus reported risksTheoretical versus reported risks Hierarchy of riskHierarchy of risk Maintaining a risk to benefit balanceMaintaining a risk to benefit balance

Conveying Risk in Broadcast Conveying Risk in Broadcast AdvertisingAdvertising

Major StatementMajor Statement Information relating to the major side Information relating to the major side

effects and contraindicationeffects and contraindication Adequate ProvisionAdequate Provision

Provides for dissemination of the PIProvides for dissemination of the PI Recognizes the inability of broadcast Recognizes the inability of broadcast

advertisements of reasonable length to advertisements of reasonable length to present and communicate this present and communicate this information effectivelyinformation effectively

Currently acceptable adequate provisionCurrently acceptable adequate provision

Conveying Risk in Professional Conveying Risk in Professional and Consumer Directed and Consumer Directed

PromotionPromotion Expect material context in direct Expect material context in direct

conjunction with claims as necessary conjunction with claims as necessary to qualify such claimsto qualify such claims

Important safety information (ISI) Important safety information (ISI) sectionsection

Incorporating risk information Incorporating risk information throughout a promotional piecethroughout a promotional piece

Common ViolationsCommon Violations

Omission of RiskOmission of Risk Minimization of RiskMinimization of Risk Broadening of IndicationBroadening of Indication Overstatement of EfficacyOverstatement of Efficacy Superiority ClaimsSuperiority Claims

Omission of Risk Omission of Risk InformationInformation

Promotional materials that make Promotional materials that make product claims must also provide risk product claims must also provide risk informationinformation

Risk information should include Risk information should include Contraindications, Warnings, Contraindications, Warnings, Precautions, pertinent Adverse Precautions, pertinent Adverse EventsEvents

Complete or partial omission of riskComplete or partial omission of risk

Minimization of Risk Minimization of Risk InformationInformation

Omission of material information about a Omission of material information about a risk described in the approved labelingrisk described in the approved labeling

Inclusion of non-risk information in a risk Inclusion of non-risk information in a risk section, or vice versasection, or vice versa

Risk information as a benefitRisk information as a benefit FramingFraming Layout/prominenceLayout/prominence SequenceSequence

Enforcement Example – EmbedaEnforcement Example – Embeda™™ (morphine sulfate and naltrexone (morphine sulfate and naltrexone

HCl)HCl) Warning LetterWarning Letter Video news releasesVideo news releases Indication Indication

Extended-release oral formulation of Extended-release oral formulation of morphine sulfate and naltrexone HCl for morphine sulfate and naltrexone HCl for the management of moderate to severe the management of moderate to severe painpain

REMS due to its potential for abuse, REMS due to its potential for abuse, misuse, overdose and addictionmisuse, overdose and addiction

Embeda - RisksEmbeda - Risks

Number of serious risks, many of which are Number of serious risks, many of which are potentially fatalpotentially fatal

Risk profile mimics that of morphine and Risk profile mimics that of morphine and naltrexone, despite the unique PK naltrexone, despite the unique PK characteristics characteristics

Boxed Warning – potentially fatal overdosing Boxed Warning – potentially fatal overdosing if capsules are chewed, crushed, dissolved, if capsules are chewed, crushed, dissolved, or co-ingested with alcoholic beveragesor co-ingested with alcoholic beverages

““Embeda can be abused in a manner similar Embeda can be abused in a manner similar to other opioid agonists, legal or illicit.”to other opioid agonists, legal or illicit.”

Embeda – Risks (continued)Embeda – Risks (continued)

Respiratory depressionRespiratory depression Respiratory arrestRespiratory arrest ApneaApnea Circulatory depressionCirculatory depression Cardiac arrestCardiac arrest HypotensionHypotension ShockShock

Embeda - Embeda - PharmacodynamicsPharmacodynamics

Clinical significance of the degree of Clinical significance of the degree of reduction in drug liking and euphoria reduction in drug liking and euphoria reported in clinical trials has not reported in clinical trials has not been establishedbeen established

NO evidence that the naltrexone in NO evidence that the naltrexone in Embeda reduces the abuse liability of Embeda reduces the abuse liability of EmbedaEmbeda

Embeda – Violative ClaimsEmbeda – Violative Claims

““EMBEDAEMBEDA™ is the first opioid approved by the ™ is the first opioid approved by the FDA with pharmacological properties FDA with pharmacological properties developed in response to the need for opioid developed in response to the need for opioid analgesics that could reduce drug liking and analgesics that could reduce drug liking and euphoria when tampered with by crushing or euphoria when tampered with by crushing or chewing.”chewing.”

““If crushed or chewed, the naltrexone within If crushed or chewed, the naltrexone within EMBEDA™ is released and absorbed with the EMBEDA™ is released and absorbed with the morphine. Naltrexone reverses the subjective morphine. Naltrexone reverses the subjective and analgesic effects of morphine…”and analgesic effects of morphine…”

Embeda’s ISIEmbeda’s ISI

Each promotional piece contained a Each promotional piece contained a section of important safety information, section of important safety information, but it failed to disclose the potential for but it failed to disclose the potential for FATAL risks associated with Embeda.FATAL risks associated with Embeda.

Stated that Embeda should not be Stated that Embeda should not be crushedcrushed Failed to mention that such action results in Failed to mention that such action results in

a rapid release and absorption of a a rapid release and absorption of a potentially fatal dose of morphinepotentially fatal dose of morphine

Embeda - OutcomeEmbeda - Outcome

Given the acute public health hazard, Given the acute public health hazard, rare action of calling the sponsor rare action of calling the sponsor prior to issuing the letterprior to issuing the letter

These and all promotional pieces with These and all promotional pieces with same or similar claims discontinuedsame or similar claims discontinued Press release removed from websitePress release removed from website

Corrective news releaseCorrective news release Distributed to similar number of media Distributed to similar number of media

outlets and distribution listsoutlets and distribution lists

Enforcement Example – Enforcement Example – Cymbalta (duloxetine HCl) Cymbalta (duloxetine HCl)

CapsulesCapsules Untitled LetterUntitled Letter Direct-to-consumer print Direct-to-consumer print

advertisementadvertisement Indicated for the management of Indicated for the management of

fibromyalgiafibromyalgia Risks include a Boxed Warning for Risks include a Boxed Warning for

suicidality, contraindications for suicidality, contraindications for concomitant use with MAOI and concomitant use with MAOI and patients with narrow-angle glaucomapatients with narrow-angle glaucoma

Does This Ad Have a Risk Does This Ad Have a Risk Problem?Problem?

Numerous efficacy claims for Numerous efficacy claims for CymbaltaCymbalta

No risk in the main body of the adNo risk in the main body of the ad Risk presentation separated by Risk presentation separated by

magazine breakmagazine break Paragraph format of risk presentation Paragraph format of risk presentation

in reduced font size quite distinct in reduced font size quite distinct from the efficacy claimsfrom the efficacy claims

What’s the Issue with What’s the Issue with IndocinIndocin®®??

IndocinIndocin®® - The Fine Print - The Fine Print

It’s in the Details…It’s in the Details…

Omission of additional risks described in Omission of additional risks described in the approved labelingthe approved labeling

Includes information from the Boxed Includes information from the Boxed Warning, but fails to include any other risksWarning, but fails to include any other risks Other risks are serious and potentially FATAL Other risks are serious and potentially FATAL

Material facts regarding dosing and Material facts regarding dosing and administration to prevent serious, administration to prevent serious, irreversible and potentially fatal adverse irreversible and potentially fatal adverse reactionsreactions

Tools of the Trade in Tools of the Trade in Evaluating Risk in PromotionEvaluating Risk in Promotion

Federal Food, Drug and Cosmetic ActFederal Food, Drug and Cosmetic Act Code of Federal RegulationsCode of Federal Regulations GuidancesGuidances The PIThe PI The Competitor’s PIThe Competitor’s PI

Contact InformationContact Information

DDMAC’s websiteDDMAC’s websitehttp://www.fda.gov/AboutFDA/http://www.fda.gov/AboutFDA/

CentersOffices/ CDER/ucm090142.htmCentersOffices/ CDER/ucm090142.htm

Phone and Fax NumbersPhone and Fax NumbersPhone: (301) 796-1200Phone: (301) 796-1200

Fax: (301) 847-8444 or (301) 847-8445Fax: (301) 847-8444 or (301) 847-8445

QuestionsQuestions